Icosapent Ethyl Lowers Revasc Rates Across the Board: REDUCE-IT Data

Adding to the list of benefits associated with icosapent ethyl (Vascepa; Amarin), new REDUCE-IT trial data show the prescription omega-3 fatty acid formulation consistently lowers the risk of revascularization—both PCI and CABG—among statin-treated patients with high triglyceride levels and either established cardiovascular disease or diabetes plus risk factors.

The benefit extends across elective, emergent, and urgent procedures as well as to first and subsequent revascularization, Benjamin E. Peterson, MD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), reported yesterday during the Society for Cardiovascular Angiography and Interventions (SCAI) meeting.

“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he told those watching the live session online.

REDUCE-IT principal investigator Deepak Bhatt, MD (Brigham and Women’s Hospital), asked by TCTMD for a potential mechanism to explain why revascularization was so uniformly reduced, pointed out that patients with higher serum levels of eicosapentaenoic acid (EPA), the drug’s key ingredient, tend to have fewer adverse outcomes.

“So I think it’s EPA that’s driving these benefits,” he said. “Now the question you could of course ask is: ‘How is EPA doing that?’” There’s evidence to suggest that EPA can stabilize cell membranes and modify plaque regression, Bhatt observed.

Study co-author Subodh Verma, MD, PhD (University of Toronto, Canada), in an email to TCTMD, described the approximately 40% decrease in CABG seen with icosapent ethyl as “mind-boggling and something that has not been observed in any other contemporary trial that I am aware of.” What's clear, said Verma, is that the drug “is doing something so formidable to the atherosclerosis process . . . that it is able to alter the natural history of the disease.”

Approved in December 2019 by the US Food and Drug Administration for the reduction of MI, stroke, coronary revascularization, and unstable angina, icosapent ethyl has previously been shown as protective against not only first-time but also recurrent CV events.

Most Cases Urgent or Emergent

Here, in a prespecified subanalysis dubbed REDUCE-IT REVASC, investigators led by Peterson focused their sights on revascularization.

Of the 8,179 patients randomized in the main trial, 11.2% underwent either PCI or CABG. The revascularized patients were more likely to have established CVD and be male, white, and from “Westernized Regions.” They also were more apt to be on intensive cholesterol-lowering therapies and taking ezetimibe. Compared with nonrevascularized patients, their triglyceride levels were “slightly higher” and HDL cholesterol “slightly lower,” said Peterson, but the two groups’ LDL cholesterol levels were similar.

On Kaplan-Meier analysis, those given the omega-3 pill (4 g/day) were less likely to undergo revascularization over long-term follow-up than those in the placebo group. “Visual curve separation was almost immediate,” he pointed out, adding that “as far as we are aware this is the first non-LDL intervention to result in a significant reduction in CABG.”

Risk of First Revascularization Over 5.7-Year Follow-up

Independent predictors of higher revascularization risk included prior PCI, male sex, diabetes, and higher baseline levels of triglycerides and high-sensitivity C-reactive protein. Additional calculations showed the risk of subsequent revascularizations to be approximately halved with icosapent ethyl.

“The main limitation of this study is that coronary revascularization as an endpoint can be considered subjective,” Peterson acknowledged. Countering this idea, though, is the fact that 58.4% of first revascularizations were urgent or emergent, suggesting they occurred in the context of ACS. Moreover, “each subtype of revascularization was similarly and statistically reduced,” he added, and endpoints were adjudicated by an independent, blinded, clinical events committee.

It’s our job as interventionalists to make sure that we’re doing secondary prevention. Timothy Henry

Commenting after the presentation, Steven R. Bailey, MD (UT Health San Antonio, TX), said, “I think it’s exciting to see. It speaks to what we think is the primary mechanism of acute myocardial infarction: plaque rupture.”

Cindy Grines, MD (Northside Hospital Cardiovascular Institute, Atlanta, GA), asked what might be behind the drop in recurrent revascularizations: were these related to de novo lesions or restenosis? “That’s a great question,” said Peterson, noting that interim data from the ongoing EVAPORATE trial suggested a decrease in total plaque among patients treated with icosapent ethyl versus placebo. “But we don’t have a lot of follow-up yet, so more information is to come on that question,” he added.

For Timothy Henry, MD (The Christ Hospital, Cincinnati, OH), also a panelist in the session, the consistent decrease in revascularization risk is compelling. Next up, “how do we increase uptake in terms of utilization? . . . I think it’s our job as interventionalists to make sure that we’re doing secondary prevention.”

Peterson agreed, saying: “Hopefully this can drive home the message that it’s really time to start thinking seriously about using this particular combination of high-dose EPA in folks who’ve had disease, especially now that we’re seeing that these findings are consistent even at the lowest ranges of triglycerides and we’re starting to understand the pleiotropic effects.”